Synthesis of diethyl{[5-(3-fluorophenyl)-pyridine-2yl]methyl}phosphonate

ABSTRACT

This application discloses a novel process for the preparation of phosphonate esters useful as intermediates in the preparation of himbacine analogs, themselves useful as thrombin receptor antagonists. The chemistry taught herein can be exemplified by the following scheme:  
                 
 
wherein R 9  is selected from alkyl, aryl heteroaryl and arylalkyl groups having 1 to 10 carbon atoms, and R 11  is selected independently for each occurrence from alkyl, aryl heteroaryl and arylalkyl groups having 1 to 10 carbon atoms and hydrogen, X 2  is Cl, Br, or I; X 3  is selected from Cl and Br; and PdL n  is a supported palladium metal catalyst or a soluble heterogeneous palladium catalyst. The L-derivatizing reagent is a moiety which converts the alcohol functional group of compound 137D to any leaving group which can be displaced by a triorgano-phosphite phosphonating agent.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is based on and claims the priority of U.S. ProvisionalApplication No. 60/817867 filed Jun. 30, 2006, which is incorporated byreference herein in its entirety.

FIELD OF THE INVENTION

This application discloses a novel process in the preparation ofdialkyl{[5-(3-fluorophenyl)-pyridine-2-yl]alkyl} phosphonate compoundswhich are useful in the synthesis of himbacine analogs, themselvesuseful as thrombin receptor antagonists.

BACKGROUND OF THE INVENTION

As described in copending U.S. patent application Ser. No. 11/331,324,filed Jan. 12, 2006 (herein, “the '324 application”), the disclosure ofwhich is incorporated herein in its entirety by reference, himbacineanalogs are useful as thrombin receptor antagonists. Thrombin is knownto have a variety of activities in different cell types. Thrombinreceptors are known to be present in such diverse cell types as humanplatelets, vascular smooth muscle cells, endothelial cells, andfibroblasts. Thrombin receptor antagonists may be useful in thetreatment of thrombotic, inflammatory, atherosclerotic andfibroproliferative disorders, as well as other disorders in whichthrombin and its receptor play a pathological role, for example, asdescribed in U.S. Pat. No. 6,063,847, the disclosure of which isincorporated by reference. Additional examples of thrombin receptorantagonists useful in the treatment of thrombotic, inflammatory,atherosclerotic, and fibroproliferative disorders, and the synthesis ofthese compounds, are described in published U.S. Patent Application No.2003/0216437 (herein, “the '437 publication”), the disclosure of whichis incorporated herein in its entirety by reference.

One thrombin receptor antagonist identified is an orally bioavailablecompound derived from himbacine having the structure of the compound 11:

Processes for the synthesis of this and similar himbacine analogthrombin receptor antagonists are disclosed in U.S. Pat. No. 6,063,847,and U.S. publication no. 2003/0216437, methods of using thrombinreceptor antagonists are disclosed in U.S. publication no. 2004/0192753,and the synthesis of the bisulfate salt of a particular himbacine analogis disclosed in U.S. publication no. 2004/0176418, the disclosures ofwhich are incorporated by reference herein.

As described in the '324 application mentioned herein above, compound 11may be synthesized from Compound 15:

by treatment with compound 16 in accordance with Scheme I.

Compound 15 is in turn prepared from compound 1:

wherein R₅ and R₆ are each independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl,alkylaryl, arylalkyl, and heteroaryl groups, in four steps in accordancewith the synthesis scheme shown in the copending '324 application, whichsynthetic schemes are incorporated herein by reference.

The copending '324 application describes the preparation of compound 16in accordance with Scheme II, below.

With reference to Scheme II, L is a leaving group selected fromhalogens, esters, sulfonates and phosphates, R⁹ is selected from alkyl,aryl heteroaryl and arylalkyl groups having 1 to 10 carbon atoms, andR¹¹ is selected from alkyl, aryl heteroaryl and arylalkyl groups having1 to 10 carbon atoms and hydrogen. As described in the '324 application,in the scheme for preparation of compound 16, compound 36 is convertedto compound 37 by first treatment with sodium carbonate to liberate thepyridyl alcohol free base, and the alcohol is subsequently reacted toconvert the hydroxyl group to a leaving group (L) which can be displacedby a phosphite reagent to form the corresponding phosphonate ester.Accordingly, as described in the '324 application, preferably compound37 is prepared by heating a solution of the alcohol intermediateisolated from compound 36 with a reagent that converts the hydroxylfunctional group to a leaving group which can be displaced by adiorgano-phosphite compound. Preferably, L is a halogen, preferably Cl,and is preferably prepared by treating the alcohol with a halogenationreagent, for example, PBr₃, PCl₃, PCl₅, and thionyl chloride, preferablythionyl chloride, followed by quenching the reaction with sodiumcarbonate, and extracting the product into toluene.

Compound 37 contained in the toluene extract is converted to compound 38by reacting a solution of compound 37 with a diorgano-phosphite in thepresence of a strong base, for example, a metal alkyl, for example,lithium alkyl and a metal amide, for example lithium bis(trimethylsilyl)amide.

The conversion of compound 38 to compound 16 is done by reactingcompound 38 with boronate, the reaction catalyzed by a palladiumcatalyst. The catalyst used can be a homogeneous catalyst, for example,a palladium phosphine, for example, palladium tristriphenyl phosphine,and palladium tris-ortho-tolyphosphine, and amine catalysts, forexample, bispalladium-trisbipyridine, or a heterogeneous catalyst, forexample, palladium supported on carbon black.

The scheme presented in the '345 application for the synthesis ofcompound 16, a critical intermediate in the preparation of a variety ofthrombin receptor antagonists, requires isolation or extraction ofintermediates in two of the four steps, and utilizes in one step apowerful base and a water sensitive diorgano-phosphite compound.Moreover, the step shown in Scheme II of reacting unisolated compound 38with boronate to form compound 16 proved to provide variable results,rendering the process of Scheme II undesirable for use in thepreparation of commercial quantities of material.

OBJECTIVES

In view of the foregoing, what is needed is a synthetic scheme usefulfor preparing compounds critical to the preparation of thrombin receptorantagonists. Particularly needed is a synthetic scheme which utilizessafer materials and provides reaction steps and processes affordingpractical scale up to a batch size suitable for commercial scalepreparation and requires minimal equipment for isolation andpurification of intermediates and products and improved product yield.These and other objectives and/or advantages are provided by the presentinvention.

SUMMARY OF THE INVENTION

In one embodiment, the present invention is a novel, simple process ofmaking dialkyl{[5-(3-fluorophenyl)-pyridine-2-yl]methyl} phosphonatecompounds (compounds having the structure of compound 116) which areuseful in the synthesis of himbacine analogs that have utility asthrombin receptor antagonist compounds:

wherein R⁹ is selected from alkyl, aryl, heteroaryl, and arylalkylgroups having 1 to 10 carbon atoms, the process comprising:

(a) reacting (5-halo-pyridin-2-yl)-methanol of the Formula 137A

with an X¹ halogenating agent, to produce a compound of the formula ofcompound 137,

where X¹ is the same for each occurrence and is selected from Cl or Brand X² is selected independently from Cl, Br, or I;

(b) reacting compound 137 with a phosphite compound of the structure ofFormula A

to produce compound 138

wherein R⁹ is as defined above;

(c) treating compound 138 with HX³ , where X³ is selected from Cl andBr, to precipitate the corresponding hydrohalide salt of Formula 138 A

(d) reacting the hydrohalide salt from step “c” with a3-flurophenylboronate compound of the structure of Formula B

wherein R¹¹ is selected independently for each occurrence from alkyl,aryl heteroaryl and arylalkyl groups having 1 to 10 carbon atoms andhydrogen, optionally in the presence of a palladium catalyst to producecompound 116.

Preferably, the halogenating agent used in step “c” is selected from achlorinating agent (therefore X¹ is Cl) or a brominating agent(therefore X¹ is Br) selected from OSCl₂, PCl₃, PCl₅, POCl₃, O₂SCl₂,(OCCl)₂, OSBr₂, PBr₃, PBr₅, POBr₃, O₂SBr₂, (OCBr)₂, more preferably thehalogenating agent is thionyl chloride (therefore X¹ is Cl). Preferably,the phosphite compound used in step “b” is a trialkyl phosphite, morepreferably, triethyl phosphite. Preferably the boronate compound used instep “d” is 3-fluoro-phenyl-boronic acid. When a catalyst is used in thereaction of step “d”, preferably the catalyst is palladium supported oncarbon black. Preferably, a catalyst is used in step “d”.

In some embodiments of the present invention, the method of the presentinvention for the preparation of a compound of the structure of compound116 is part of a larger reaction scheme for the preparation of athrombin receptor antagonist having the structure of compound 11, asshown below in Scheme III.

wherein the halogenating agent is selected from a chlorinating agent (X¹is Cl) selected from OSCl₂, PCl₃, PCl₅, POCl₃, O₂SCl₂, (OCCl)₂, and abrominating (X¹ is Br) selected from OSBr₂, PBr₃, PBr₅, POBr₃, O₂SBr₂,(OCBr)₂; X¹ is the same for each occurrence and is selected, based onthe halogenating agent chosen, from Cl or Br; X² is Cl, Br, or I; X³ isselected from Cl and Br; R¹ is a linear, branched or cyclic alkyl,preferably having from 1 to about 4 carbon atoms, more preferably C₂H₅—;R⁹ is selected from alkyl, aryl, heteroaryl, and arylalkyl groups having1 to 10 carbon atoms; and R¹¹ is selected independently for eachoccurrence from alkyl, aryl heteroaryl and arylalkyl groups having 1 to10 carbon atoms and hydrogen. In some embodiments, the halogenatingagent is preferably thionyl chloride, X¹ and X³ are preferably Cl and X²is preferably Br. In some embodiments R9 is preferably C₂H₅—. In someembodiments the phosphite compound used is preferably a trialkylphosphite, more preferably, triethyl phosphite. Preferably the boronatecompound used is 3-fluoro-phenyl-boronic acid.

These and other aspects and advantages of the invention will be apparentfrom the following description.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions and terms are used herein or are otherwiseknown to a skilled artisan. Except where stated otherwise, thedefinitions apply throughout the specification and claims. Chemicalnames, common names and chemical structures may be used interchangeablyto describe the same structure. These definitions apply regardless ofwhether a term is used by itself or in combination with other terms,unless otherwise indicated. Hence, the definition of “alkyl” applies to“alkyl” as well as the “alkyl” portions of “hydroxyalkyl,” “haloalkyl,”“alkoxy,” etc.

Unless otherwise known, stated or shown to be to the contrary, the pointof attachment for a multiple term substituent (two or more terms thatare combined to identify a single moiety) to a subject structure isthrough the last named term of the multiple term substituent. Forexample, a cycloalkylalkyl substituent attaches to a targeted structurethrough the latter “alkyl” portion of the substituent (e.g.,structure-alkyl-cycloalkyl).

The identity of each variable appearing more than once in a formula maybe independently selected from the definition for that variable, unlessotherwise indicated.

Unless stated, shown or otherwise known to be the contrary, all atomsillustrated in chemical formulas for covalent compounds possess normalvalencies. Thus, hydrogen atoms, double bonds, triple bonds and ringstructures need not be expressly depicted in a general chemical formula.

Double bonds, where appropriate, may be represented by the presence ofparentheses around an atom in a chemical formula. For example, acarbonyl functionality, —CO—, may also be represented in a chemicalformula by —C(O)—, or —C(═O)—. One skilled in the art will be able todetermine the presence or absence of double (and triple bonds) in acovalently-bonded molecule. For instance, it is readily recognized thata carboxyl functionality may be equivalently represented by —COOH,—C(O)OH, —C(═O)OH or —CO₂H.

The term “heteroatom,” as used herein, means a nitrogen, sulfur oroxygen atom. Multiple heteroatoms in the same group may be the same ordifferent.

As used herein, the term “alkyl” means an aliphatic hydrocarbon groupthat can be straight or branched and comprises 1 to about 24 carbonatoms in the chain. Preferred alkyl groups comprise 1 to about 15 carbonatoms in the chain. More preferred alkyl groups comprise 1 to about 6carbon atoms in the chain. “Lower alkyl” means alkyl groups of 1 to 6carbon atoms in the chain. “Branched” means that one or more lower alkylgroups such as methyl, ethyl or propyl, are attached to a linear alkylchain. The alkyl can be substituted by one or more substituentsindependently selected from the group consisting of halo, aryl,cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, —NH(alkyl),—NH(cycloalkyl), —N(alkyl)₂ (which alkyls can be the same or different),carboxy and —C(O)O-alkyl. Non-limiting examples of suitable alkyl groupsinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl,heptyl, nonyl, decyl, fluoromethyl, trifluoromethyl andcyclopropylmethyl.

“Alkenyl” means an aliphatic hydrocarbon group (straight or branchedcarbon chain) comprising one or more double bonds in the chain and whichcan be conjugated or unconjugated. Useful alkenyl groups can comprise 2to about 15 carbon atoms in the chain, preferably 2 to about 12 carbonatoms in the chain, and more preferably 2 to about 6 carbon atoms in thechain. The alkenyl group can be substituted by one or more substituentsindependently selected from the group consisting of halo, alkyl, aryl,cycloalkyl, cyano and alkoxy. Non-limiting examples of suitable alkenylgroups include ethenyl, propenyl, n-butenyl, 3-methylbut-enyl andn-pentenyl.

Where an alkyl or alkenyl chain joins two other variables and istherefore bivalent, the terms alkylene and alkenylene, respectively, areused.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Useful alkoxy groups can comprise 1 to about 12carbon atoms, preferably 1 to about 6 carbon atoms. Non-limitingexamples of suitable alkoxy groups include methoxy, ethoxy andisopropoxy. The alkyl group of the alkoxy is linked to an adjacentmoiety through the ether oxygen.

The term “cycloalkyl” as used herein, means an unsubstituted orsubstituted, saturated, stable, non-aromatic, chemically-feasiblecarbocyclic ring having preferably from three to fifteen carbon atoms,more preferably, from three to eight carbon atoms. The cycloalkyl carbonring radical is saturated and may be fused, for example, benzofused,with one to two cycloalkyl, aromatic, heterocyclic or heteroaromaticrings. The cycloalkyl may be attached at any endocyclic carbon atom thatresults in a stable structure. Preferred carbocyclic rings have fromfive to six carbons. Examples of cycloalkyl radicals includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or thelike.

“Alkynyl” means an aliphatic hydrocarbon group comprising at least onecarbon-carbon triple bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkynyl groups have about 2 to about 10 carbon atoms in the chain; andmore preferably about 2 to about 6 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkynyl chain. Non-limiting examples ofsuitable alkynyl groups include ethynyl, propynyl, 2-butynyl,3-methylbutynyl, n-pentynyl, and decynyl. The alkynyl group may besubstituted by one or more substituents which may be the same ordifferent, each substituent being independently selected from the groupconsisting of alkyl, aryl and cycloalkyl.

The term “aryl,” as used herein, means a substituted or unsubstituted,aromatic, mono- or bicyclic, chemically-feasible carbocyclic ring systemhaving from one to two aromatic rings. The aryl moiety will generallyhave from 6 to 14 carbon atoms with all available substitutable carbonatoms of the aryl moiety being intended as possible points ofattachment. Representative examples include phenyl, tolyl, xylyl,cumenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, or the like. Ifdesired, the carbocyclic moiety can be substituted with from one tofive, preferably, one to three, moieties, such as mono- throughpentahalo, alkyl, trifluoromethyl, phenyl, hydroxy, alkoxy, phenoxy,amino, monoalkylamino, dialkylamino, or the like.

“Heteroaryl” means a monocyclic or multicyclic aromatic ring system ofabout 5 to about 14 ring atoms, preferably about 5 to about 10 ringatoms, in which one or more of the atoms in the ring system is/are atomsother than carbon, for example nitrogen, oxygen or sulfur. Mono- andpolycyclic (e.g., bicyclic) heteroaryl groups can be unsubstituted orsubstituted with a plurality of substituents, preferably, one to fivesubstituents, more preferably, one, two or three substituents (e.g.,mono- through pentahalo, alkyl, trifluoromethyl, phenyl, hydroxy,alkoxy, phenoxy, amino, monoalkylamino, dialkylamino, or the like).Typically, a heteroaryl group represents a chemically-feasible cyclicgroup of five or six atoms, or a chemically-feasible bicyclic group ofnine or ten atoms, at least one of which is carbon, and having at leastone oxygen, sulfur or nitrogen atom interrupting a carbocyclic ringhaving a sufficient number of pi (π) electrons to provide aromaticcharacter. Representative heteroaryl (heteroaromatic) groups arepyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, benzofuranyl,thienyl, benzothienyl, thiazolyl, thiadiazolyl, imidazolyl, pyrazolyl,triazolyl, isothiazolyl, benzothiazolyl, benzoxazolyl, oxazolyl,pyrrolyl, isoxazolyl, 1,3,5-triazinyl and indolyl groups.

The term “heterocyclic ring” or “heterocycle,” as used herein, means anunsubstituted or substituted, saturated, unsaturated or aromatic,chemically-feasible ring, comprised of carbon atoms and one or moreheteroatoms in the ring. Heterocyclic rings may be monocyclic orpolycyclic. Monocyclic rings preferably contain from three to eightatoms in the ring structure, more preferably, five to seven atoms.Polycyclic ring systems consisting of two rings preferably contain fromsix to sixteen atoms, most preferably, ten to twelve atoms. Polycyclicring systems consisting of three rings contain preferably from thirteento seventeen atoms, more preferably, fourteen or fifteen atoms. Eachheterocyclic ring has at least one heteroatom. Unless otherwise stated,the heteroatoms may each be independently selected from the groupconsisting of nitrogen, sulfur and oxygen atoms.

The terms “Hal,” “halo,” “halogen” and “halide,” as used herein, mean achloro, bromo, fluoro or iodo atom radical. Chlorides, bromides andfluorides are preferred halides.

The term “carbonate”, as used herein, is understood to includebicarbonates.

The term “isomer”, as used herein, is understood to mean one of two ormore molecules having the same number and kind of atoms and hence thesame molecular weight, but differing in respect to the arrangement orconfiguration of the atoms.

The term “epimerizing”, as used herein, is understood to mean convertingfrom one isomer to another, wherein it is the relative position of anattached H that differs between the two isomers.

The term “precipitate”, as used herein, is understood to mean to fallout of solution as a solid. Precipitation applies equally to theformation of an insoluble salt “in situ”, or changing the solubilityproperties of a solvent. Examples of changing the solubility propertiesof a solvent include cooling the solution and the addition of asufficient amount of an “anti-solvent” to a solution such thatprecipitated compound has reduced solubility in the combined solvents.

The term “dynamic resolution”, as used herein, is understood to mean aprocess in which a conversion from a first isomer to a second isomer ofthe same compound in a solution is thermodynamically driven by thedepletion of the second isomer from the solution by precipitation of thesecond isomer.

The following abbreviations are defined: EtOH is ethanol; Me is methyl;Et is ethyl; Bu is butyl; n-Bu is normal-butyl, t-Bu is tert-butyl, OAcis acetate; KOt-Bu is potassium tert-butoxide; NBS is N-bromosuccinimide; NMP is 1-methyl-2-pyrrolidinone; DMAP is4-dimethylaminopyridine; THF is tetrahydrofuran; DBU is1,8-diazabicyclo[5,4,0]undec-7-ene; DMA is N,N-dimethylacetamide;n-BU₄NBr is tetrabutylammonium bromide; n-Bu₄NOH is tetrabutylammoniumhydroxide, n-Bu₄NH₂SO₄ is tetrabutylammonium hydrogen sulfate, and“equiv.” or “eq.” means equivalents.

The term “n”, as it is used herein, is understood to be an integerhaving a value that is inclusive of the range recited thereafter. Thus“n is between 0 and 4” and “n ranges 0-4” both mean that n may have anyof the values 0, 1, 2, 3 or 4.

As mentioned above, copending U.S. patent application Ser. No.11/331,324 (herein, “the '324 application”) describes the synthesis ofcompounds of the structure of compound 11 which have promising activityas thrombin receptor inhibitors.

As illustrated below in Schemes IV and V, the '324 application describesin detail the synthesis of compound 11 and related compounds, whichsynthesis is incorporated herein by reference.

A critical intermediate in the synthesis of compound 11 are compoundshaving the structure of compound 16 and related phoshonate esters(herein, sometimes referred to for convenience as the compounds havingthe structure of compound 116). The inventors have surprisinglydiscovered a process for the synthesis of the compounds having thestructure of compound 116 which uses less active reagents and simplifiesunit operations in each synthetic step over a process for thepreparation of compounds having the structure of compound 116 describedin the '324 application. In particular, improvements in yield,specificity, and product purity are realized by isolation of5-halo-pyridin-2-yl-methyl phosphonate ester (139), and by selection ofa triorganophosphite phosphonating agent in the conversion of compound137 to compound 138. Moreover, utilizing these process steps, thecurrent invention process results in a greater overall yield ofcompounds having the structure of compound 116 based on the startingpyridyl alcohol, 75% overall yield for the process of the presentinvention compared with an overall yield of 60% for the processdescribed in the '324 application.

The overall reaction scheme of the present invention is schematicallydepicted in Scheme VI.

wherein R⁹ is selected from alkyl, aryl heteroaryl and arylalkyl groupshaving 1 to 10 carbon atoms, and R¹¹ is selected independently for eachoccurrence from alkyl, aryl heteroaryl and arylalkyl groups having 1 to10 carbon atoms and hydrogen, X² is Cl, Br, or I; X³ is selected from Cland Br; and PdL_(n) is a supported palladium metal catalyst or a solubleheterogeneous palladium catalyst. The L-derivatizing reagent can be ahalogenating agent (thus L is a halogen), for example, a chlorinatingagent, for example, OSCl₂, PCl₃, PCl₅, POCl₃, O₂SCl₂, (OCCl)₂ (thus L isCl), and a brominating agent, for example OSBr₂, PBr₃, PBr₅, POBr₃,O₂SBr₂, (OCBr)₂ (thus, L is Br). As will be appreciated, theL-derivatizing reagent can also be a moiety which converts the alcoholfunctional group to any leaving group which can be displaced by thephosphonating agent (triorgano-phosphite) used to covert compound 137Dto compound 138D, for example a sulfonylester (provided by, for example,benzensulfonyl chloride L-derivatizing reagent), a sulfonate ester, andthe L-derivatizing reagents described in the copending '324 application,(incorporated herein by reference).

Although all steps of Reaction Scheme VI can be carried outindividually, and the intermediate prepared in each phase isolated, itis advantageous in the present reaction scheme to utilize intermediatecompound 137 “in situ” in the reaction medium obtained after workup foruse in the next step, the conversion from the halide to the phosphonate(compound 138).

Each step of reaction Scheme VI will be discussed next.

The first step of the process of the invention is conversion of apyridyl hydroxyalkyl to the correspondind phosphono-alkyl. This isillustrated in Scheme VI as the first step, conversion of compound 136to compounds of the structure 138. In the first step of Scheme VI, thealcohol functional group of [(5-(halo)-2-hydroxymethyl]-pyridine, where“halo” is selected from bromine, chlorine and iodine, is reacted insolution with an L-derivatizing reagent, as mentioned above, forexample, a chlorinating agent, for example OSCl₂, PCl₃, PCl₅, POCl₃,O₂SCl₂, (OCCl)₂ (thus L is Cl), a brominating agent, for example OSBr₂,PBr₃, PBr₅, POBr₃, O₂SBr₂, (OCBr)₂ (thus, L is Br), and a sulfonatingagent, thus L is a sulfonyl ester, to provide the corresponding5-Bromo-2-(L)methyl-pyridine, preferably,5-Bromo-2-(halo)methyl-pyridine, where “halo” is preferably Cl, Br, andI. Although any of the above-mentioned L-derivatizing agents aresuitable for the process of the invention, it is preferable to usethionyl chloride. It will be appreciated that other L-derivatizingagents not specifically mentioned herein may also be used in the processof the present invention. Any suitable solvent system may be employed,preferably a solvent system comprising non-protic solvents of moderatepolarity, for example a mixture of toluene and acetonitrile (MeCN). Itis preferable to carry out the reaction in a temperature range of fromabout 0° C. to about 70° C., more preferably from about 20° C. to about50° C., more preferably at about 45° C. Preferably the initialconcentration of the alcohol substrate is from about 0.5 M to about 0.9M. Preferably, the chlorinating agent is used at least in a 1.5-foldexcess based on the alcohol substrate.

It is preferable to run the reaction until the alcohol has beencompletely consumed. The reaction can be monitored for completeconversion of the alcohol, for example, by HPLC or gas chromatographictechniques. At the end of the reaction, optionally the reaction mixtureis quenched with an aqueous base. It is particularly preferred to quenchthe reaction when it is being carried out on a large scale. When aquench step is included in the reaction, preferably, the reaction isquenched using a potassium carbonate solution. Following completion ofthe reaction, the organic layer of the reaction mixture is separated,washed and concentrated.

Thus obtained, the concentrate is charged into a suitable apparatus andcombined with triorgano-phosphite compound having the structure ofFormula A, wherein R⁹ is selected independently for each occurrence fromalkyl, aryl heteroaryl and arylalkyl groups having 1 to 10 carbon atoms.

Preferably, R⁹ is the same for all occurrences and is alkyl, morepreferably linear alkyl, more preferably ethyl.

The reaction mixture is heated and maintained at a temperature to drivethe reaction, preferably to a temperature of from about 130° C. to about150° C . After a sufficient period of maintaining the reaction mixtureat a suitable temperatrue, preferably until complete conversion of themethyl-L derivatized substrate (the compound 137D for example, when achlorinating L-derivatizing reagent is employed, a methylchloridesubstrate) the reaction mixture is cooled and treated with hydrochloricacid to convert the phosphonate (compound 138D) into the correspondinghydrochloride salt (compound 139D). Preferably, the temperature of thereaction mixture is maintained at less than about 20° C. during thistreatment. Although HCl treatment can be carried out using anyconventional means, for example, by bubbling HCl gas through thereaction mixture, or treating the mixture with an HCl solution, it isconvenient to treat the reaction mixture by stirring it with an HClsolution, preferably an HCl/isopropanol solution.

After the salt is formed, it begins to precipitate from the reactionmixture. Heptanes are added to complete the salt precipitation andimprove the yield of salt recovered from the reaction mixture. It ispreferred to keep the reaction mixture at a temperature of less thanabout 20° C. during this addition. The phosphonate hydrohalide salt(compound 139D) is then recovered from the reaction mixture by vacuumfiltration, washed and vacuum dried for use in the synthesis of compound116.

In the last step of Scheme VI, compound 116 is synthesized from thephosphonate hydrochloride salt by reacting it with a3-fluorophenylboronate of the structure of the compound of Formula B:

where R¹¹ is selected independently for each occurrence from alkyl, arylheteroaryl and arylalkyl groups having 1 to 10 carbon atoms andhydrogen.

Although it will be appreciated that any 3-fluorophenyl boronate can bereacted with the (5-halo-pyrid-2-yl)-methylphosphonate salt compound(139D), it is preferred to use 3-fluoroboronic acid (thus R¹¹ for eachoccurrence is H). It is preferred to carry this reaction out in a twophase reaction medium, one aqueous and one organic, preferably isobutylacetate. Accordingly, the reaction is carried out by providing anaqueous boronic acid solution/slurried with a supported palladiumcatalyst, for example, palladium supported on carbon black, for example,Degussa 5% Pd/C type E 105 CA/W. Conversion of the phosphonatehydrochloride salt (compound 139D) can be followed by HPLC assay. It ispreferred to maintain reaction conditions until the HPLC analysisindicates complete conversion of the starting phosphonate. It ispreferred to maintain the reaction mixture at a temperature of fromabout 70° C. to about 80° C. during the reaction. It is preferred toinitiate the reaction with the starting phosphonate (compound 139D)present at a concentration of about 0.5 M to about 1.0 M, and use atleast a 1.3-fold excess of the boronate reagent. Workup of the reactionmixture includes removing excess boronic acid by adjusting the mixtureto a basic pH, preferably a pH of from about pH 11 to about pH 13,separating the organic layer by splitting, and removing processimpurities by washing the batch with a 2% aqueous NaCl solution, andconcentrating the organic layer. During workup, it is preferred tomaintain the reaction mixture at a temperature of from about 20° C. toabout 30° C. Product, compound 116, is obtained by anti-solventprecipitation, for example, by treating the organic phase with asufficient volume of heptanes until the product precipitates fromsolution.

With reference to Scheme IV, it will be appreciated that theintermediate compounds of Formula 116 can be prepared by reactingintermediate compounds of Formula 139d with other organometallicreactants in place of boronates, for example, but not limited to:fluoroaryl-alkylboranes; fluoroaryl-haloboranes; fluoroaryl- zinc,-aluminium, -magnesium, and -tin reagents, and other organometallicreagents represented by formula

where “M” is an organometallic reagent capable of displacing the X²halogen of compound 138 with a 3-fluoroaryl moiety.

The starting alcohol, 5-bromo-2-hydroxymethyl-pyridine, compound 136,may be prepared from 5-bromo-2methyl-pyridine-N-oxide. This synthesis isdisclosed in detail in the copending '324 application, which isincorporated herein in its entirety by reference. It will be appreciatedthat the present invention process can be carried out using variouslysubstituted hydroxymethyl pyridines, as well as5-bromo-2hydroxymethyl-pyridine obtained by any other means.

There follows an example preparation of[5-(3-Fluoro-phenyl)-pyridin-2-ylmethyl]-phosphonic acid diethyl ester(compound 16) which illustrates, but in no way limits, the presentinvention.

EXAMPLE

The following solvents and reagents may be referred to by theirabbreviations in parenthesis:

-   ethyl acetates: EtOAc-   methanol: MeOH-   isopropanol: IPA-   tertiarybutyl-methyl ether: TBMEsodium bistrimethylsilylamide:    NaHMDS-   triethyl amine: TEA-   trifluoro acetic acid: TFA-   tertiary-butoxycarbonyl: t-BOC-   tetrahydrofuran: THF-   lithium bis(trimethylsilyl)amide: LiHMDS-   mole: mol.-   HPLC—high pressure liquid chromatography

Example 1 Preparation of[5-(3-Fluoro-phenyl)-pyridin-2-ylmethyl]-phosphonic acid diethyl ester

To a reaction vessel was charged (100 g, 0.29 mol) of phosphonatecompound 139 (where R⁹ is ethyl- for all occurrences), 5% Pd/C 50% wet(5.0 g), 3-fluorophenylboronic acid (61 g; 0.44 mol) and sodiumcarbonate (100 g; 0.94 mol). 600 ml of iso-butyl acetate was charged andthe mixture agitated. 400 ml of water was charged, and the agitatedmixture was heated to 70-80° C. for at least 3 h at which time an HPLCassay indicated complete reaction. Upon completion, the reaction mixturewas cooled to 25° C. and filtered to remove the Pd/C catalyst. Thecatalyst cake was washed with 200 ml iso-butyl acetate (combined withthe filtrate/batch) and 100 ml water (waste). 25% sodium hydroxidesolution was used to adjust batch to pH 11-13. During the process thereaction mixture was maintained at a temperature of from 20° C. to 30°C. The organic layer was separated and washed with 500 ml water withagitation. A 25% sodium hydroxide solution was used to adjust the pH ofthe batch to a pH value of from pH 11 to pH13. Throughout the was thetemperature was maintained at a value of from about 20° C. to about 30°C.

After washing the layers were separated and the organic layer was washedwith 300 ml of 2% sodium chloride solution with 10-15 minutes withagitation. The layers were separated and an HPLC assay of the organiclayer indicated impurities were reduced to a desirable level. Darco (10g) was added to the organic layer. The resultant slurry was agitated for1 hour, and then filtered to remove the de-coloring agent. The filtercake was washed with 200 ml iso-butyl acetate (combined with thefiltrate/batch) and the batch was concentrated under reduced pressure toabout 200 ml at from 40° C. to 50° C., then cooled to a temperature offrom 15° C. to 25° C. Heptanes (1000 ml) were charged into the coldconcentrate over 2.5-3 hr, maintaining the temperature at from about 15°C. to 25° C. The mixture was cooled to a temperature of from −15° C. to−5° C. over 3 hr and agitated at the same temperature for 1 hr. Thecrystalline solid was filtered, washed with 200 ml heptanes, and driedovernight under vacuum at a temperature of from about 25° C. to 35° C.to provide 70.37 g (75%). Mp 61-63° C. ¹H NMR (CDCl₃) δ 1.3 (t, J=7.05Hz, 6H), 3.47 (d, J=22.02 Hz, 2H), 4.12 (q, J=7.08 Hz, 4H), 7.10 (ddd,J=8.42, 2.55, 0.88, Hz, 1H), 7.28 (ddd, J=9.85, 2.36, 1.80 Hz, 1 H),7.36 (dt, J=7.86, 1.27, Hz, 1H), 7.46 (m, 1H), 7.83 (ddd, J=8.1, 2.2,0.32 Hz, 1H), 8.76 (d, J=2.38, 1H).

Example 1A Preparation of [(5-Bromo-Pyridin-2-ylMethyl)-Phosphonic AcidDiethyl Ester] Hydrochloride

Into a solution of 5-bromo-2-hydroxymethyl-pyridine (BHMP, 50.0 g, 266mmol) in toluene (100 mL) and MeCN (150 mL) was added thionyl chloride(35.0 mL, 57.1 g, 479 mmol). This reaction mixture was stirred at 45° C.for 4 hours. Toluene (250 mL) was added to the reaction mixture and thereaction mixture was cooled to 0° C. The reaction was quenched with 20%potassium carbonate solution (450 ml), keeping the temperature below 30°C. The reaction mixture was stirred for 10 min and the layers werepartitioned. The organic layer was washed once with water (100 mL) andthe organic layer was concentrated under reduced pressure to a volume ofabout 200 mL. The concentrated crude solution was transferred to adistillation apparatus. At room temperature, triethyl phosphite (200 mL,1144 mmol) was added to the crude concentrated solution and the reactionmixture was heated to 145° C. until reaction was completed. Distillatedriven off of the reaction mixture during the heating period wascollected (˜200 mL). After 12 hours of heating the reaction mixture wascooled to 0° C. A solution of 5-6N HCl in isopropanol (150 mL) wasslowly added to the cooled reaction mixture over a period of 1 hour,keeping the internal temperature below 5° C. Heptanes (350 mL) were thenadded to the mixture over 1 hours and the resultant slurry was stirredfor another hour. The solid product was collected by vacuum filtration,washed with 10% IPA/heptanes and dried under vacuum at room temperatureto provide 81 g of product (89%). Mp. 118-120° C. ¹H NMR (400 MHz,CDCl₃) δ 1.29 (t, J=7.05 Hz, 6H), 3.88 (d, J=22.3 Hz, 2H), 4.19 (m, 4H),7.88 (dd, J=8.57 Hz, 1H), 8.34 (dd, J=8.55, 2.18 Hz, 1H), 8.71 (s, 1H).

Preparation of Starting Material: 5-bromo-2-hydroxymethylpyridine

The starting alcohol (5-bromo-2hydroxymethylpyridine) used above inExample 1 was prepared in two steps.Step I

To a solution of 5-bromo-2-methylpyridine N-oxide (10.0 g, 5.32 mmol) inEtOAc (50.0 ml) at 0° C. was added dropwise trifluoroacetic anhydride(9.8 ml, 6.92 mmol.) while keeping the temperature below 50° C. Afterthe completion of the addition, the mixture was heated to a temperatureof from 75° C. to 80° C. and stirred for at least 1 h. An HPLC assay ofthe mixture indicated the reaction was complete when5-bromo-2-methylpyridine N-oxide was present a less than 5% of itsinitial value.

Upon completion, the mixture was cooled below 50° C. and MeOH (10.0 ml)was added. The mixture was heated for at least 1 h at 50° C. Thesolution was concentrated under vacuum and MeOH was removed bydisplacement with EtOAc (40.0 ml) and concentrated to a volume of 30 ml.To the concentrate was added toluene (20.0 ml) and the solution cooledto −10° C. over 2 h. The crystalline solid was filtered and washed withcold toluene and dried overnight under vacuum at 35° C. to provide 10.1g (63%) of product. Mp 89-92° C. ¹H NMR (DMSO-d₆) δ 4.56 (s, 2 H), 7.49(d, 1 H), 8.1 (dd, J=2.3, 2.3 Hz, 1 H), 8.64 (d, J=2.1Hz, 1H).Step II

A slurry of compound 36 (10.0 g, 33.1 mmol) in TBME (100 ml) was treatedwith 20% potassium carbonate (20 ml) solution and stirred at roomtemperature for 1 h. The layers were separated and the organic layer waswashed with water. The solution thus obtained was concentrated to ˜10 mLvolume and 20 mL heptanes was added at 45-50 C. Solution was cooled to20-25 C and additional 20 mL heptanes was charged. Reaction was agitatedat 20-25 C for 2 hours and filtered. Product was dried overnight undervacuum at 15-25 C to give 5.0 g (80%) of product. ¹H NMR (CDCl₃) δ 3.36(bs, Hz, 1 —OH), 4.75 (d, J=9.07 Hz, 2H), 7.21 (d, J=8.31 Hz, 1H), 7.83(d, J=8.28 Hz, 1H), 8.64 (d, J=1.89 Hz, 1H).

The above description of the invention is intended to be illustrativeand not limiting. Various changes or modifications in the embodimentsdescribed herein may occur to those skilled in the art. These changescan be made without departing from the scope or spirit of the invention

1. A process for making a compound having the structure of compound 11:

wherein R1 is an alkyl group of from 1 to about 4 carbon atoms, theprocess comprising: (a) reacting (5-halo-pyridin-2-yl)-methanol of theFormula 137A

where X² is selected independently from Cl, Br, or I; with an X¹halogenating agent, to produce a compound of the formula of compound137,

where X¹ is the same for each occurrence and is selected from Cl or Brand X² is as defined above; (b) reacting compound 137 with a phosphitecompound of the structure of Formula A:

wherein R⁹ is selected from alkyl, aryl, heteroaryl, and arylalkylgroups having 1 to 10 carbon atoms, to produce compound 138:

wherein R⁹ is as defined above; (c) treating compound 138 with HX³ ,where X³ is selected from Cl and Br, to precipitate the correspondinghydrohalide salt of Formula 138 A

(d) reacting the hydrohalide salt from step “c” with a3-flurophenylboronate compound of the structure of Formula B

wherein R¹¹ is selected independently for each occurrence from alkyl,aryl heteroaryl and arylalkyl groups having 1 to 10 carbon atoms andhydrogen, optionally in the presence of a palladium catalyst to producecompound
 116. 2. A process for making a compound having the structure ofcompound 11:

wherein R1 is an alkyl group of from 1 to about 4 carbon atoms, theprocess comprising: (a) reacting (5-Bromo-2-methoxy-pyridine) with achlorinating agent selected from OSCl₂, PCl₃, PCl₅, to produce acompound of the formula of compound
 137.

(b) reacting compound 137 with a phosphite compound of the structure ofFormula A

to produce compound 138

wherein R⁹ is separately selected for each occurrence from alkyl, aryl,heteroaryl, and arylalkyl groups having 1 to 10 carbon atoms; (c)treating compound 138 with HCl to obtain the corresponding hydrochloridesalt; (d) reacting the hydrochloride salt from step “c” with3-flurophenylboronic acid, optionally in the presence of a palladiumcatalyst to produce compound having the structure of compounds 16,

(e) reacting the compound 116 formed in step “d” with a compound of thestructure of compound 15,

to yield compound
 11. 3. The process of claim 2 wherein the phosphitecompound used in step “b” is a trialkyl phosphate.
 4. The process ofclaim 2 wherein the phosphite used in step “b” is triethyl phosphite. 5.A process for making a compound of the structure of compound 116

wherein R⁹ is separately selected for each occurrence from alkyl, aryl,heteroaryl, and arylalkyl groups having 1 to 10 carbon atoms, theprocess comprising: reacting a hydrochloride salt compound having thestructure of compound 139, where R⁹ is as defined above,

with 3-flurophenylboronic acid in the presence of a palladium catalyst.6. The process of claim 5 wherein compound 139 is provided by (a)reacting the hydrochloride salt of the structure of compound 137

with a phosphite compound of the structure of Formula A

wherein R⁹ is separately selected for each occurrence from alkyl, aryl,heteroaryl, and arylalkyl groups having 1 to 10 carbon atoms; and (b)treating the reaction product from step “a” with HCl to obtain compound139.
 7. The process of claim 6 wherein the phosphite compound used instep “a” is a trialkyl phosphite.
 8. The process of claim 7 wherein thetrialkyl phosphite used in step “a” is triethyl phosphite.
 9. Theprocess of claim 5 further comprising after the “treating” step “b”, thestep of precipitating the phosphonate hydrochloride formed in step “b”by adding an antisolvent to the reaction mixture containing thephosphonate hydrochloride compound of structure
 139. 10. The process ofclaim 1 wherein said palladium catalyst is palladium metal supported oncarbon black.
 11. The process of claim 1 wherein said palladium catalystis a soluble palladium catalyst.
 12. A process for making a compound ofthe structure of compound 116

wherein R⁹ is separately selected for each occurrence from alkyl, aryl,heteroaryl, and arylalkyl groups having 1 to 10 carbon atoms, theprocess comprising: (a) reacting (5-halo-pyridin-2-yl)-methanol of theFormula 137A

where X² is selected independently from Cl, Br, or I; with an X¹halogenating agent, to produce a compound of the formula of compound137,

where X¹ is the same for each occurrence and is selected from Cl or Brand X² is as defined above; (b) reacting compound 137 with a phosphitecompound of the structure of Formula A,

wherein R⁹ is selected from alkyl, aryl, heteroaryl, and arylalkylgroups having 1 to 10 carbon atoms, to produce compound 138,

wherein R⁹ is as defined above; (c) treating compound 138 with HX³ ,where X³ is selected from Cl and Br, to precipitate the correspondinghydrohalide salt of Formula 138A,

wherein R⁹ is as defined above; and (d) reacting the hydrohalide saltfrom step “c” with a 3-flurophenylboronate compound of the structure ofFormula B

wherein R¹¹ is selected independently for each occurrence from alkyl,aryl heteroaryl and arylalkyl groups having 1 to 10 carbon atoms andhydrogen, optionally in the presence of a palladium catalyst to producecompound
 116. 13. A process for making a compound of the structure ofcompound 116

wherein R⁹ is separately selected for each occurrence from alkyl, aryl,heteroaryl, and arylalkyl groups having 1 to 10 carbon atoms, theprocess comprising: (a) reacting (5-halo-pyridin-2-yl)-methanol of theFormula 137A

where X² is selected independently from Cl, Br, or 1, with an X¹halogenating agent, to produce a compound of the formula of compound137,

where X¹ is the same for each occurrence and is selected from Cl or Brand X² is as defined above; (b) reacting compound 137 with a phosphitecompound of the structure of Formula A,

wherein R⁹ is selected from alkyl, aryl, heteroaryl, and arylalkylgroups having 1 to 10 carbon atoms, to produce compound 138,

wherein R⁹ is as defined above; (c) treating compound 138 with HX³ ,where X³ is selected from Cl and Br, to precipitate the correspondinghydrohalide salt of Formula 138A,

wherein R⁹ is as defined above; and (d) reacting the hydrohalide saltfrom step “c” with an organometallic compound capable of displacing X²of Formula 138A with a 3-flurophenyl moiety of Formula B′,

to produce compound
 116. 14. The process of claim 13 wherein theorganometallic compound used in step “d” is selected from the groupconsisting of: fluoroaryl-alkylboranes; fluoroaryl-haloboranes; andfluoroaryl- zinc, -aluminium, -magnesium, and -tin reagents.
 15. Theprocess of claim 1 wherein the phosphite used in step “b” is triethylphosphite.
 16. The process of claim 2 wherein said palladium catalyst isselected from palladium metal supported on carbon black and a solublepalladium catalyst.
 17. The process of claim 3 wherein said palladiumcatalyst is selected from palladium metal supported on carbon black anda soluble palladium catalyst.
 18. The process of claim 4 wherein saidpalladium catalyst is selected from palladium metal supported on carbonblack and a soluble palladium catalyst.
 19. The process of claim 5wherein said palladium catalyst is selected from palladium metalsupported on carbon black and a soluble palladium catalyst.
 20. Theprocess of claim 6 wherein said palladium catalyst is selected frompalladium metal supported on carbon black and a soluble palladiumcatalyst.
 21. The process of claim 7 wherein said palladium catalyst isselected from palladium metal supported on carbon black and a solublepalladium catalyst.
 22. The process of claim 8 wherein said palladiumcatalyst is selected from palladium metal supported on carbon black anda soluble palladium catalyst.
 23. The process of claim 9 wherein saidpalladium catalyst is selected from palladium metal supported on carbonblack and a soluble palladium catalyst.
 24. The process claim 5 furthercomprising after the “treating” step “b”, the step of precipitating thephosphonate hydrochloride formed in step “b” by adding an antisolvent tothe reaction mixture containing the phosphonate hydrochloride compoundof structure
 139. 25. The process claim 6 further comprising after the“treating” step “b”, the step of precipitating the phosphonatehydrochloride formed in step “b” by adding an antisolvent to thereaction mixture containing the phosphonate hydrochloride compound ofstructure
 139. 26. The process claim 7 further comprising after the“treating” step “b”, the step of precipitating the phosphonatehydrochloride formed in step “b” by adding an antisolvent to thereaction mixture containing the phosphonate hydrochloride compound ofstructure
 139. 27. The process claim 8 further comprising after the“treating” step “b”, the step of precipitating the phosphonatehydrochloride formed in step “b” by adding an antisolvent to thereaction mixture containing the phosphonate hydrochloride compound ofstructure 139.